Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.
Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.
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DOI：
10.1073/pnas.2115973119
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发表时间：
2022-03-08
影响因子：
11.1
通讯作者：
Baron-Van Evercooren A
中科院分区：
文献类型：
--
作者：
Sarrazin N;Chavret-Reculon E;Bachelin C;Felfli M;Arab R;Gilardeau S;Brazhnikova E;Dubus E;Yaha-Cherif L;Lorenceau J;Picaud S;Rosolen S;Moissonnier P;Pouget P;Baron-Van Evercooren A
促进髓鞘再生已成为预防神经变性和促进多发性硬化症（MS）等白质疾病恢复的一种新的治疗途径。迄今为止，大多数这些策略都是在短期的啮齿动物脱髓鞘模型中发展起来的，脱髓鞘会自发修复。定义良好、更接近人类的非人类灵长类动物模型将使我们能够有效地推进治疗方法。在这里，我们提出了一个非人类灵长类动物视神经脱髓鞘模型，概括了多发性硬化症病变的几个特征。该模型导致髓鞘再生失败，与进行性轴突变性和视觉功能障碍相关，因此为髓鞘疾病（如多发性硬化症（MS））的临床前治疗转化为临床提供了缺失的环节，中枢神经系统（CNS）的白质疾病（如多发性硬化症（MS））导致神经传导失败和长期神经功能障碍，影响各种感觉和运动系统，包括视觉。虽然大多数疾病修饰疗法针对免疫和炎症反应，但促进髓鞘再生已成为预防神经元变性和促进恢复的新治疗途径。大多数这些策略都是在短期的啮齿动物脱髓鞘模型中发展起来的，这种模型可以自发修复，并且不能反映人类中枢神经系统的大小、组织和生物学。因此，需要定义良好的非人类灵长类动物模型来有效地推进患者的治疗方法。在这里，我们跟踪了长期毒素诱导的猕猴视神经脱髓鞘对髓鞘再生和轴突保存的影响，以及对视觉功能的影响。动眼力行为、眼科检查、电生理和视网膜成像的结果表明视力损害累及视神经和视网膜。这些视觉功能障碍在解剖学水平上与持续的视神经脱髓鞘、轴突变性和视网膜内层的改变完全相关。这个与轴突变性和视觉功能障碍相关的慢性视神经脱髓鞘的非人灵长类动物模型，概括了多发性硬化症病变的几个关键特征，并且应该有助于提供缺失的环节，将新兴的修复早髓鞘/神经保护疗法转化为临床髓鞘疾病，如多发性硬化症。
Promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery in white matter diseases, such as multiple sclerosis (MS). To date most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair. Well-defined nonhuman primate models closer to man would allow us to efficiently advance therapeutic approaches. Here we present a nonhuman primate model of optic nerve demyelination that recapitulates several features of MS lesions. The model leads to failed remyelination, associated with progressive axonal degeneration and visual dysfunction, thus providing the missing link to translate emerging preclinical therapies to the clinic for myelin disorders such as MS. White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS.
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DOI：
10.1073/pnas.1808064115
发表时间：
2018-12-11
影响因子：
11.1
作者：
Duncan, Ian D.;Radcliff, Abigail B.;Wierenga, Lauren A.
通讯作者：
Wierenga, Lauren A.
影响因子：
158.5
作者：
Chang, A;Tourtellotte, WW;Trapp, BD
通讯作者：
Trapp, BD
中枢神经系统轴突反复脱髓鞘和再髓鞘化的证明
影响因子：
12.7
作者：
JOHNSON, ES;LUDWIN, SK
通讯作者：
LUDWIN, SK
影响因子：
14.5
作者：
Brusa, A;Jones, SJ;Plant, GT
通讯作者：
Plant, GT
影响因子：
1.9
作者：
Chatziralli, Irini P.;Moschos, Marilita M.;Ladas, Ioannis D.
通讯作者：
Ladas, Ioannis D.